Mitochondrial Ultrastructural Alterations and Declined M2 Receptor Density Were Involved in Cardiac Dysfunction in Rats after Long Term Treatment with Autoantibodies against M2 Muscarinic Receptor

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Abstract

Background

Previous studies showed that autoantibodies (M ₂-AA) against the second extracellular loop of M ₂ muscarinic receptor (M ₂AChR-el2) from dilated cardiomyopathy (DCM) serum could induce DCM-like morphological changes in mice hearts. However, the effects of M ₂-AA on the cardiac function during the process of DCM and the potential mechanisms are not fully known. The present study was designed to dynamically observe the cardiac function, mitochondrial changes, and M ₂ receptor binding characteristics in rats long-term stimulated with M ₂-AA in vivo.

Methods

M ₂-AA-positive model was established by actively immunizing healthy male Wistar rats with synthetic M ₂AChR-el2 peptide for 18 months. Meanwhile, vehicle group rats were administrated with physiological saline. The change of mitochondrial membrane potential (ΔΨm) was detected by radionuclide imaging. The ultrastructure of mitochondria was observed under electron microscopy. The M ₂ receptor binding characteristics were determined by radioactive ligand binding assay.

Results

After immunization for 12 months, compared with vehicle group, M ₂AChR-el2-immunized rats showed decreased myocardial contractility and cardiac diastolic function evidenced by declined maximal rate of rise of ventricular pressure and increased left ventricular end-diastolic pressure, respectively. Additionally, mitochondrial swelling and vacuolation were observed. At 18 months, M ₂AChR-el2-immunized rats manifested significant decreased cardiac systolic and diastolic function and pathological changes such as enlargement of right ventricular cavity and wall thinning; and the mitochondrial damage was aggravated. Furthermore, the M ₂ receptor maximum binding capacity (B _max) of the M ₂AChR-el2-immunized rats significantly decreased, while the M ₂ receptor dissociation constant (K _d) was increased.

Conclusions

Our study suggested that long-term stimulation with M ₂-AA leaded to the ventricular dilatation and gradual deterioration of cardiac dysfunction. Mitochondrial damage and the down-regulation of M ₂ receptor density and affinity may be involved in the process.

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Author and article information

Contributors

Jing Ai: Role: Academic Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, CA USA )

ISSN (Electronic): 1932-6203

Publication date (Electronic): 18 June 2015

Publication date Collection: 2015

Volume: 10

Issue: 6

Electronic Location Identifier: e0129563

Affiliations

[1 ]Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, P. R. China

[2 ]The Key Laboratory of Remodeling-related Cardiovascular Diseases, Capital Medical University, Ministry of Education, Beijing, 100069, P. R. China

[3 ]Department of Physiology, School of Basic Medical Sciences, Shanxi Medical University, Taiyuan, Shanxi, 030001, P. R. China

[4 ]Department of Pathology, School of Basic Medical Sciences, Shanxi Medical University, Taiyuan, Shanxi, 030001, P. R. China

[5 ]Department of Neurology, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, 030001, P. R. China

[6 ]Beijing Key Laboratory of Metabolic Disorders Related Cardiovascular Diseases, Capital Medical University, Beijing, 100069, P. R. China

Harbin Medical University, CHINA

Author notes

Competing Interests: The authors have declared that no competing interests exist.

Conceived and designed the experiments: HL. Performed the experiments: SZ ZH Jin Wang LW YW TL. Analyzed the data: Jin Wang Jie Wang. Wrote the paper: SZ ZH Jin Wang LW YW TL HL.

* E-mail: liuhr2000@ 123456126.com

Article

Publisher ID: PONE-D-14-46939

DOI: 10.1371/journal.pone.0129563

PMC ID: 4472961

PubMed ID: 26086781

SO-VID: 64e5b15d-49a5-4c4a-b5ed-8e9b04d396e6

License:

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

History

Date received : 19 October 2014

Date accepted : 11 May 2015

Page count

Figures: 3, Tables: 2, Pages: 13

Funding

This study was supported by grants from the 973 Program Earlier Research Project (2014CB560704) to Huirong Liu ( http://program.most.gov.cn); the National Natural Science Foundation Youth Project (81300694) to Suli Zhang ( http://www.nsfc.gov.cn/); the 2013 Specialized Research Fund for Doctoral Program of Higher Education (20131107120021) to Suli Zhang ( http://www.moe.gov.cn/); and grants from the Scientific Research Base Construction-Scientific and Technological Innovation Platform-Metabolic Disorders Related Cardiovascular Diseases Research Platform Construction (municipal level) (PXM2014_014226_000038; http://www.bjedu.gov.cn/publish/portal27/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Custom metadata

Data Availability All relevant data are within the paper and its Supporting Information files.